Pregabalin is described as (S)-3-(aminomethyl)-5-methylhexanoic acid, binds to the calcium channel alpha-2-delta (α2δ) subunit and is an analog of endogenous inhibitory neurotransmitter gamma-amino butyric acid (GABA), which is involved in brain neuronal activity. The molecular formula is C8H17NO2 and the molecular weight is 159.23 g/mol. Pregabalin is a white to off-white crystalline solid with a pKa1 of about 4.2 and a pKa2 of about 10.6. It is freely soluble in water and both basic and acidic aqueous solutions. The log of the partition coefficient (n-octanol/0.05 M phosphate buffer) at pH 7.4 is about −1.35.
In the U.S. and Canada, pregabalin has been approved for the management of neuropathic pain associated with diabetic peripheral neuropathy, management of post herpetic neuralgia, management of fibromyalgia, and as an adjunctive therapy for adult patients with partial onset seizures. Pregabalin is useful as antiseizure therapy for central nervous system disorders such as epilepsy, Huntington's chorea, cerebral ischemia, Parkinson's disease, tardive dyskinesia, and spasticity. Pregabalin exhibits anti-seizure activity and is useful for treating, among other conditions, epilepsy, pain, physiological conditions associated with psychomotor stimulants, inflammation, gastrointestinal (GI) damage, alcoholism, insomnia, fibromyalgia, and various psychiatric disorders, including anxiety, depression, mania, and bipolar disorder.
Pregabalin is currently available as immediate release LYRICA™ in 25, 50, 75, 100, 150, 200, 225, and 300 mg hard shell capsules and is administered in patients two or three times daily (BID or TID).
The recommended dose of pregabalin is 100 mg three times a day (300 mg/day) for the treatment of neuropathic pain associated with diabetic peripheral neuropathy and post herpetic neuralgia.
In the management of fibromyalgia, the recommended dose of LYRICA™ is 300 to 450 mg/day. Begin dosing at 75 mg two times a day (150 mg/day). The dose may be increased to 150 mg two times a day (300 mg/day) within 1 week based on efficacy and tolerability. Pregabalin at doses of 150 to 600 mg/day is recommended for adjunctive therapy for adult patients with partial onset seizures.
Pregabalin is described in U.S. Pat. No. 6,197,819. Further, U.S. Pat. No. 6,197,819 also has a generic disclosure of pharmaceutical compositions comprising pregabalin. U.S. Pat. No. 5,563,175 describes the use of pregabalin in the treatment of seizure disorders. U.S. Pat. No. 6,117,906 discloses the use of pregabalin in treating anxiety, while U.S. Pat. No. 6,001,876 discloses its use in treating pain. U.S. Pat. Nos. 6,663,175, 5,599,973, 5,608,090, 5,684,189, 5,710,304, 5,616,793, 5,629,447, 5,637,767, 5,840,956, 6,046,353, 6,028,214 disclose processes for preparation of pregabalin and intermediates used in these processes.
Pregabalin absorption in the GI tract has a specific and short window. Most, if not all, of the known formulations are aimed primarily at gastro-retention or flotation as a pivotal means of maintaining a sustained drug release albeit applying a different polymer construct.
Gastro-retentive drug delivery may be classified into three systems, i.e., an expansion-by-swelling system, a floating or buoyant system, and a bioadhesive system. All these approaches involve the use of swelling and expanding for achieving gastric retention. These systems are usually monolithic tablets and are comprised of the drug and one or more swellable polymers. These polymers swell unrestrained via imbibition of gastric fluid to such an extent that it causes the tablet to float on gastric contents.
Furthermore, for highly soluble drugs, controlled delivery systems, which utilize hydrophilic, polymeric matrices, do not provide adequate control over the drug release rate, instead resulting in a release that approximates first-order kinetics.
There is a need for alternative therapies to overcome or mitigate at least one of the deficiencies of the prior art or to at least provide patients with a useful alternative.